Nicotine and alcohol are the most commonly abused recreational drugs, and nicotine dependence and alcoholism have a high degree of comorbidity. For example, an estimated 90% of alcoholics also smoke, and an estimated 60% of smokers engage in binge drinking. The health consequences of alcohol and nicotine abuse are severe, including many types of cancer, cardiovascular disease, liver damage, and chronic obstructive pulmonary disease. Further, these health issues are more severe in individuals who co-abuse these drugs. Therefore, it is crucial to understand the behavioral and neurobiological mechanisms that underlie the interaction between nicotine and alcohol abuse. This information can then be used to develop treatments specifically designed address the comorbidity of addiction to these drugs. A major problem with both nicotine addiction and alcoholism is the craving and relapse induced by individuals' heightened responsivity to the people, places, and other cues associated with drinking and smoking. In addition, smoking-associated cues can trigger drinking. Preliminary studies demonstrate that nicotine enhances the response alcohol-associated cues, but it is not known whether nicotine's effects on alcohol drinking are secondary to these effects. In addition, the response to many drug-associated cues involves the brain's motivational circuit, including the nucleus accumbens and the prefrontal cortex, which affect behavior in complementary ways. It may be through activation of this system that nicotine increases the response to alcohol cues, but to date no studies have examined this possibility. The proposed work will determine whether nicotine increases alcohol intake by increasing the response to alcohol cues within this system, and whether the response to alcohol cues depends upon specific subcircuits within the brain's motivational circuitry. This project will determine th behavioral and neural basis for the ability of nicotine to increase alcohol drinking in rats, by dissociating the effects of cues during specific phases of alcohol drinking, and by measuring and manipulating the activity of neurons with the brain's motivational circuitry. To this end, two sets of experiments will determine 1) which specific aspect of alcohol drinking (including the response to alcohol cues) are affected by nicotine, and 2) which specific projections are necessary and sufficient to engender alcohol cues with motivational value. Findings from this project regarding the specific behavioral and neural points of interaction between nicotine and alcohol will allow for the development of experimental and pharmacological interventions that specifically address the effect of nicotine on alcohol intake.